Field of the Invention
The invention relates to medical field, particularly novel urea compounds, preparation methods and uses thereof.
Description of Related Art
Heat shock protein 70 (Hsp70), which is widely present in nucleus, cytoplasm, endoplasmic reticulum, mitochondrion, and chloroplast cell, is involved in denovo synthesis, localization, maturation of proteins and degradation of misfolded proteins in cells, thereby affecting the growth and metabolic functions of cells. In cells, the binding of Hsp70 to nascent polypeptide on ribosomes can prevent misfolding of nascent polypeptides; Hsp70 is essential for the remodeling of clathrin during pinocytosis in mammalian cells; the binding of Hsp70 to protein in a non-natural conformation can promote the correct folding and assembly of protein, maintain the extended conformation of protein precursor and prevent aggregation, denaturation and degradation thereof, thereby facilitating the transport to organelles thereof.
Studies show that Hsp70 is associated with many diseases such as cancer, neurodegenerative disease, allogeneic graft rejection, and infection. In tumor cells, Hsp70 affects apoptosis mainly by the following pathways:
(1) Mitochondrial Pathway, wherein in early stage of mitochondrion, Hsp70 inhibits the release of cytc and AIF from mitochondrion by blocking the migration of Bax and reducing the permeability of mitochondrial outer membrane; in late stage of mitochondria, Hsp70 binds to Apaf1 directly, and suppress the aggregation of procaspase-9, which causes that apoptotic bodies cannot be formed and downstream caspase-3 cannot be activated;
(2) Death receptor pathway, wherein Hsp70 binds to Akt and PKC by inhibiting the activation of JNK, which causes that kinases are dephosphorylated, proteins are stabilized, and cells survive; similarly, Hsp70 can also bind to DR4 and DR5 to inhibit aggregation and activity of DISC induced by TRAIL;
(3) DNA degradation pathway, wherein Hsp70, Hsp40, and ICAD complex can inhibit the activity and folding effect of DNase CAD so that chromosome DNA in late apoptosis cannot be degraded, thereby achieving the anti-apoptotic effect.
Research on use of Hsp70 in tumor treatment has become a hot spot in recent years, however, inhibitors with a high activity have not been found yet, and the mechanism of action thereof is not clear yet. In tumor cells, the expression of Hsp70 and relevant proteins thereof is increased abnormally. Experiments demonstrate that after stimulation by administration of a drug, tumor cells exert potential defensing mechanism by virtue of Hsp70, and generate the drug resistance, resulting in the reduced drug activity. Hsp70 inhibitors are prospective in reversing the resistance of tumor cells to an anti-tumor drug.